the proposed international research study on mechanisims of a Chinese herbal formula on cancer pain is an extension of our ongoing parents grants funded by NIH, P01-AT002605 (9/2005 - 8/201010) and R21 AT 004113 (2/1/08 - 1/31/10). Dr. Lixing Lao, the PI is the project leader of the P01 study on acupuncture's mechanisms of action on persistent inflammatory pain and C0-I of the study on the effect of acupuncture on cancer-related pain. The proposed project will be performed in collaboration with Dr. Ling Xu at Changzheng Hospital (CZ), Shanghai, China. Pain, one of the most common and feared symptoms associated with cancer, is not yet adequately controlled. Chines herbal medicine has been used for thousands of years to treat a variety of ailments, including pain. Dr. Lao and his team have been undertaking investigations on carcionoma-induced pain, and his collaborator, Dr. Ling Xu has been investigating the effect of Traditional Chinese Medicine (TCM) on cancer-related disorders, including pain. Previous studies show that osteoclastic activitiesare involved in bone cancer pain and cause elevated levels of serum bone alkaline phosphatase (BAP) and carboxyterminal pyridlinoline cross-linked telopeptide of type 1 collagen (ICTP). Transient receptor potential channels, vanilloid subfamily member 1 (TRPV1), and TRPA1, and TRPV4 are also involved persistent pain. Our pilot studies showed that an herbal formula, TLSJ, which has been used clinically, alleviated bone cancer pain in patients and in a rat model. The objective of the proposal is to evaluate the efficacy and safety of TLSJ on cancer pain and explore its mechanisms in male and female rat models. We hypothesize that external applications of a TLSJ gel will inhibit cancer pain by suppressing osteoclast activities, evidenced by decrasig levels of serum BAP and ICTA, and TRP channel expression in dorsal root ganglia (DRG). The three aims are: Aim 1 a) To determine the effect of TLSJ Gel on cancer-induced pain in male and female rat models of bone cancer pain. Spontaneious pain, thermal hyperalgesia and mechanical hyperalgesia/allodyna will be determined following herb treatment. b) To determine the safety of TLSJ. Possible adverse effects will be studied by monitoring the animals for behavioral changes, and the toxicity of the formula will be determined by biochemical assay and histological examination. Aim 2. To investigate effects of TLSJ Gel on osteoclasic activity and BAP and ICTP levels during cancer pain. Bone osteeoclastic activity will be hisologically examined. Serum BAP and ICTP will be measured using ELISA. Aim e. To investigate effects of TLSJ Gel on TRP channel expression. TRPV1, TRPA1 and TRPV4 antagonists will be used to characterize TRP involvement in bone cancer pain. DRG expression of the three channels will be examined by immunohistochemical staining. The success of the experiments will provide preliminary data for designing clinical trials to study the effects of Chinese herbs on persistent cancer pain. This will facilitate the development of effective and safe alternative/complementary treatment for cancer pain. PUBLIC HEALTH RELEVANCE: Pain occurs frequently incancerpatients and has not been controlled adequately. Acupuncture has been used for millennia to treat pain. This study will evaluate the effects and mechanisms of an herb formula Tongluo Sanjie (TLSJ) on such pain in rat models. The success of the proposed study will greatly advance the management of cancer pain.